POS1118 METFORMIN AS A POTENTIAL DISEASE-MODIFYING DRUG IN OSTEOARTHRITIS: A SYSTEMATIC REVIEW OF PRE-CLINICAL AND HUMAN STUDIES
Authors: Y. Lim, Y. Wang, M. Estee, J. Abidi, M. Udaya Kumar, S. M. Hussain, A. Wluka, C. Little, F. Cicuttini
Journal: Annals of the Rheumatic Diseases (2022)

Background Osteoarthritis causes significant pain and disability with no approved disease-modifying drugs. There is evidence emerging from pre-clinical and human studies suggesting metformin may have disease-modifying properties in osteoarthritis 1-5 . Given its pleiotropic effects and safety profile, metformin has the potential to be a novel therapy for osteoarthritis. Objectives We systematically reviewed the evidence from both pre-clinical and human studies for the potential disease-modifying effect of metformin in osteoarthritis. Methods Ovid Medline, Embase and CINAHL were searched between inception and June 2021 using MeSH terms and key words to identify studies examining the association between metformin use and outcome measures related to osteoarthritis. Two reviewers performed the risk of bias assessment and 3 reviewers extracted data independently. Qualitative evidence synthesis was performed. This systematic review is registered on PROSPERO (CRD42021261052 and CRD42021261060). Results Fifteen (10 pre-clinical and 5 human) studies were included. Most studies (10 pre-clinical and 3 human) assessed the effect of metformin using knee osteoarthritis models. In pre-clinical studies, metformin was assessed for the effect on structural outcomes (n=10); immunomodulation (n=5); pain (n=4); and molecular pathways of its effect in osteoarthritis (n=7). For human studies, metformin was evaluated for the effect on structural progression (n=3); pain (n=1); and immunomodulation (n=1). Overall, pre-clinical studies consistently showed metformin having a chondroprotective, immunomodulatory and analgesic effect in osteoarthritis, predominantly mediated by adenosine monophosphate-activated protein kinase activation. Evidence from human studies, although limited, was consistent with findings in pre-clinical studies. Conclusion We found consistent evidence across pre-clinical and human studies to support a favourable effect of metformin on chondroprotection, immunomodulation and pain reduction in knee osteoarthritis. Further high-quality clinical trials are needed to confirm these findings as metformin could be a novel therapeutic drug for the treatment of osteoarthritis. References [1]Li H, Ding X, Terkeltaub R, Lin H, Zhang Y, Zhou B, et al. Exploration of metformin as novel therapy for osteoarthritis: preventing cartilage degeneration and reducing pain behavior. Arthritis Res Ther. 2020;22(1):34. [2]Li J, Zhang B, Liu WX, Lu K, Pan H, Wang T, et al. Metformin limits osteoarthritis development and progression through activation of AMPK signalling. Ann Rheum Dis. 2020;79(5):635-645. [3]Na HS, Kwon JY, Lee SY, Lee SH, Lee AR, Woo JS, et al. Metformin Attenuates Monosodium-Iodoacetate-Induced Osteoarthritis via Regulation of Pain Mediators and the Autophagy-Lysosomal Pathway. Cells. 2021;10(3). [4]Lu CH, Chung CH, Lee CH, Hsieh CH, Hung YJ, Lin FH, et al. Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan. PLoS ONE [Electronic Resource]. 2018;13(1):e0191242. [5]Wang Y, Hussain SM, Wluka AE, Lim YZ, Abram F, Pelletier JP, et al. Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the Osteoarthritis Initiative-a prospective cohort study. Arthritis research &amp; therapy. 2019;21(1):127. Disclosure of Interests Yuan Lim: None declared, Yuanyuan Wang: None declared, Mahnuma Estee: None declared, Jawad Abidi: None declared, Maushmi Udaya Kumar: None declared, Sultana Monira Hussain: None declared, Anita Wluka: None declared, Christopher Little Grant/research support from: CBL receives research funding from pharmaceutical companies (Fidia Farmaceutici, Cynata Therapeutics, Ceva Animal Health Pty Ltd and Regeneus Pty Ltd) to investigate efficacy of novel osteoarthritis therapeutics in pre-clinical models, through specific services/testing-contract research agreements between and managed by The University of Sydney or the Northern Sydney Local Health District, Flavia Cicuttini: None declared